Faculty Bibliography

We describe the spatiotemporal course of cortical high-gamma activity, hippocampal ripple activity and interictal epileptiform discharges during an associative memory task in 15 epilepsy patients undergoing invasive EEG. Successful encoding trials manifested significantly greater high-gamma activity in hippocampus and frontal regions. Successful cued recall trials manifested sustained high-gamma activity in hippocampus compared to failed responses. Hippocampal ripple rates were greater during successful encoding and retrieval trials. Interictal epileptiform discharges during encoding were associated with 15% decreased odds of remembering in hippocampus (95% confidence interval 6-23%). Hippocampal interictal epileptiform discharges during retrieval predicted 25% decreased odds of remembering (15-33%). Odds of remembering were reduced by 25-52% if interictal epileptiform discharges occurred during the 500-2000-ms window of encoding or by 41% during retrieval. During encoding and retrieval, hippocampal interictal epileptiform discharges were followed by a transient decrease in ripple rate. We hypothesize that interictal epileptiform discharges impair associative memory in a regionally and temporally specific manner by decreasing physiological hippocampal ripples necessary for effective encoding and recall. Because dynamic memory impairment arises from pathological interictal epileptiform discharge events competing with physiological ripples, interictal epileptiform discharges represent a promising therapeutic target for memory remediation in patients with epilepsy.

OBJECTIVE:Brain functions such as perception, motor control, learning, and memory arise from the coordinated activity of neuronal assemblies distributed across multiple brain regions. While major progress has been made in understanding the function of individual neurons, circuit interactions remain poorly understood. A fundamental obstacle to deciphering circuit interactions is the limited availability of research tools to observe and manipulate the activity of large, distributed neuronal populations in humans. Here we describe the development, validation, and dissemination of flexible, high-resolution, thin-film (TF) electrodes for recording neural activity in animals and humans. APPROACH/METHODS:We leveraged standard flexible printed-circuit manufacturing processes to build high-resolution TF electrode arrays. We used biocompatible materials to form the substrate (liquid crystal polymer; LCP), metals (Au, PtIr, and Pd), molding (medical-grade silicone), and 3D-printed housing (nylon). We designed a custom, miniaturized, digitizing headstage to reduce the number of cables required to connect to the acquisition system and reduce the distance between the electrodes and the amplifiers. A custom mechanical system enabled the electrodes and headstages to be pre-assembled prior to sterilization, minimizing the setup time required in the operating room. PtIr electrode coatings lowered impedance and enabled stimulation. High-volume, commercial manufacturing enables cost-effective production of LCP-TF electrodes in large quantities. MAIN RESULTS/RESULTS:Our LCP-TF arrays achieve 25× higher electrode density, 20× higher channel count, and 11× reduced stiffness than conventional clinical electrodes. We validated our LCP-TF electrodes in multiple human intraoperative recording sessions and have disseminated this technology to >10 research groups. Using these arrays, we have observed high-frequency neural activity with sub-millimeter resolution. SIGNIFICANCE/CONCLUSIONS:Our LCP-TF electrodes will advance human neuroscience research and improve clinical care by enabling broad access to transformative, high-resolution electrode arrays.

BACKGROUND:Many electroencephalography (EEG) based seizure detection paradigms have been developed and validated over the last two decades. The majority of clinical approaches use scalp or intracranial EEG electrodes. Scalp EEG is limited by patient discomfort and short duration of useful EEG signals. Intracranial EEG involves an invasive surgical procedure associated with significant risk making it unsuitable for widespread use as a practical clinical biometric. A less invasive EEG monitoring approach, that is between invasive intracranial procedures and noninvasive methods, would fill the need of a safe, accurate, chronic (ultra-long term) and objective seizure detection method. We present validation of a continuous EEG seizure detection paradigm using human single-channel EEG recordings from subcutaneously placed electrodes that could be used to fulfill this need. METHODS:Ten-minute long sleep, awake and ictal EEG epochs obtained from 21 human subjects with subscalp electrodes and validated against simultaneous iEEG recordings were analyzed by three experienced clinical neurophysiologists. The 201subscalp EEG time series epochs where classified as diagnostic for awake, asleep, or seizure by the clinicians who were blinded to all other information. Seventy of the epochs were classified in this way as representing seizure activity. A subject specific seizure detection algorithm was trained and then evaluated offline for each patient in the data set using the expert consensus classification as the gold standard. RESULTS:The average seizure detection performance of the algorithm across 21 subjects exceeded 90 % accuracy: 97 % sensitivity, 91 % specificity, and 93 % accuracy. For 19 of 21 patient datasets the algorithm achieved 100 % sensitivity. For 15 of 21 patients, the algorithm achieved 100 % specificity. For 13 of 21 patients the algorithm achieved 100 % accuracy. COMPARISON/UNASSIGNED:No comparable published methods are available for subgaleal EEG seizure detection. CONCLUSIONS:These findings suggest that a simple seizure detection algorithm using subcutaneous EEG signals could provide sufficient accuracy and clinical utility for use in a low power, long-term subcutaneous brain monitoring device. Such a device would fill a need for a large number of people with epilepsy who currently have no means for accurately quantifying their seizures thereby providing important information to healthcare providers not currently available.

Sensory input arrives in continuous sequences that humans experience as segmented units, e.g., words and events. The brain's ability to discover regularities is called statistical learning. Structure can be represented at multiple levels, including transitional probabilities, ordinal position, and identity of units. To investigate sequence encoding in cortex and hippocampus, we recorded from intracranial electrodes in human subjects as they were exposed to auditory and visual sequences containing temporal regularities. We find neural tracking of regularities within minutes, with characteristic profiles across brain areas. Early processing tracked lower-level features (e.g., syllables) and learned units (e.g., words), while later processing tracked only learned units. Learning rapidly shaped neural representations, with a gradient of complexity from early brain areas encoding transitional probability, to associative regions and hippocampus encoding ordinal position and identity of units. These findings indicate the existence of multiple, parallel computational systems for sequence learning across hierarchically organized cortico-hippocampal circuits.

Patients with drug-resistant focal onset epilepsy are not always suitable candidates for resective surgery, a definitive intervention to control their seizures. The alternative surgical treatment for these patients in Japan has been vagus nerve stimulation (VNS). Besides VNS, epileptologists in the United States can choose a novel palliative option called responsive neurostimulation (RNS), a closed-loop neuromodulation system approved by the US Food and Drug Administration in 2013. The RNS System continuously monitors neural electroencephalography (EEG) activity at the possible seizure onset zone (SOZ) where electrodes are placed and responds with electrical stimulation when a pre-defined epileptic activity is detected. The controlled clinical trials in the United States have demonstrated long-term utility and safety of the RNS System. Seizure reduction rates have continued to improve over time, reaching 75% over 9 years of treatment. The incidence of implant-site infection, the most frequent device-related adverse event, is similar to those of other neuromodulation devices. The RNS System has shown favorable efficacy for both mesial temporal lobe epilepsy (TLE) and neocortical epilepsy of the eloquent cortex. Another unique advantage of the RNS System is its ability to provide chronic monitoring of ambulatory electrocorticography (ECoG). Valuable information obtained from ECoG monitoring provides a better understanding of the state of epilepsy in each patient and improves clinical management. This article reviews the developmental history, structure, and clinical utility of the RNS System, and discusses its indications as a novel palliative option for drug-resistant epilepsy.

How do firing patterns in a cortical circuit change when inhibitory neurons are excited? We virally expressed an excitatory designer receptor exclusively activated by a designer drug (Gq-DREADD) in all inhibitory interneuron types of the CA1 region of the hippocampus in the rat. While clozapine N-oxide (CNO) activation of interneurons suppressed firing of pyramidal cells, unexpectedly the majority of interneurons also decreased their activity. CNO-induced inhibition decreased over repeated sessions, which we attribute to long-term synaptic plasticity between interneurons and pyramidal cells. Individual interneurons did not display sustained firing but instead transiently enhanced their activity, interleaved with suppression of others. The power of the local fields in the theta band was unaffected, while power at higher frequencies was attenuated, likely reflecting reduced pyramidal neuron spiking. The incidence of sharp wave ripples decreased but the surviving ripples were associated with stronger population firing compared with the control condition. These findings demonstrate that DREADD activation of interneurons brings about both short-term and long-term circuit reorganization, which should be taken into account in the interpretation of chemogenic effects on behavior.

OBJECTIVE:The combined spatiotemporal dynamics underlying sign language production remains largely unknown. To investigate these dynamics as compared to speech production we utilized intracranial electrocorticography during a battery of language tasks. METHODS:We report a unique case of direct cortical surface recordings obtained from a neurosurgical patient with intact hearing and bilingual in English and American Sign Language. We designed a battery of cognitive tasks to capture multiple modalities of language processing and production. RESULTS:We identified two spatially distinct cortical networks: ventral for speech and dorsal for sign production. Sign production recruited peri-rolandic, parietal and posterior temporal regions, while speech production recruited frontal, peri-sylvian and peri-rolandic regions. Electrical cortical stimulation confirmed this spatial segregation, identifying mouth areas for speech production and limb areas for sign production. The temporal dynamics revealed superior parietal cortex activity immediately before sign production, suggesting its role in planning and producing sign language. CONCLUSIONS:Our findings reveal a distinct network for sign language and detail the temporal propagation supporting sign production.

High frequency oscillations (HFOs) are bursts of neural activity in the range of 80 Hz or higher, recorded from intracranial electrodes during epileptiform discharges. HFOs are a proposed biomarker of epileptic brain tissue and may also be useful for seizure forecasting. Despite such clinical utility of HFOs, the spatial context and neuronal activity underlying these local field potential (LFP) events remains unclear. We sought to further understand the neuronal correlates of ictal high frequency LFPs using multielectrode array recordings in the human neocortex and mesial temporal lobe during rhythmic onset seizures. These multiscale recordings capture single cell, multiunit, and LFP activity from the human brain. We compare features of multiunit firing and high frequency LFP from microelectrodes and macroelectrodes during ictal discharges in both the seizure core and penumbra (spatial seizure domains defined by multiunit activity patterns). We report differences in spectral features, unit-local field potential coupling, and information theoretic characteristics of high frequency LFP before and after local seizure invasion. Furthermore, we tie these time-domain differences to spatial domains of seizures, showing that penumbral discharges are more broadly distributed and less useful for seizure localization. These results describe the neuronal and synaptic correlates of two types of pathological HFOs in humans and have important implications for clinical interpretation of rhythmic onset seizures.

PURPOSE/OBJECTIVE:Surgical planning for people with drug resistant non-lesional focal epilepsy can be challenging. Prior studies focus on cases that are only MRI-negative or MRI-negative with PET-positive imaging, but little is known about outcomes in patients with non-lesional findings on both MRI and PET imaging. In this study, we investigate 5-year surgical outcomes in patients who underwent epilepsy surgery for drug resistant MRI/PET-negative focal epilepsy. METHODS:We collected clinical and testing data on 131 consecutive patients with drug resistant non-lesional epilepsy who were presented at a multidisciplinary epilepsy surgery conference at the New York University Comprehensive Epilepsy Center between 2010 and 2014, and identified those who underwent epilepsy surgery in order to review 5-year surgical outcomes. RESULTS:There were 103 with non-lesional MRI studies, and of these, 22 had corresponding non-lesional PET imaging. 14 MRI/PET-negative patients pursued a surgical treatment option and 9 underwent resections after intracranial EEG. At 5 years, 77.8 % of patients had favorable (ILAE class 1 and 2) outcomes. Most (77.8 %) had focal cortical dysplasia type Ia (FCDIa) on pathology. CONCLUSION/CONCLUSIONS:These findings suggest that with careful planning and patient selection, surgery for patients with drug resistant MRI/PET-negative focal epilepsy can be successful.